Genomes and Genes

Species

Interaction of fetal growth and bisphenol A in obesity

Summary

Principal Investigator: Frederick S vom Saal

Abstract: DESCRIPTION (provided by applicant): There continues to be controversy concerning the "obesogen" hypothesis, which proposes that exposure to certain environmental chemicals during critical periods in development is contributing to the dramatic increase in obesity that has occurred over the last two decades. We have developed a novel mouse model that results in siblings produced by hemiovariectomized mothers that range from intrauterine growth restricted (IUGR) to macrosomic based on location in one crowded uterine horn. The IUGR mice experience a dramatic 90% increase in body weight, while macrosomic males only experience a 30% increase in body weight, during the first week after weaning, after which IUGR and macrosomic males remain significantly heavier than males with a median body weight at birth. Adult IUGR mice show marked similarities to IUGR humans in terms of glucose intolerance, elevated insulin as well as an increase in total abdominal fat weight, but have markedly fewer gonadal fat pad adipocytes and markedly different gene expression profiles relative to equally obese macrosomic mice. Perinatal exposure to very low doses of BPA results in a significant increase in body weight in adulthood but a decrease in adult gonadal fat pad adipocyte and glucose intolerance, similar to untreated IUGR males, but very different from untreated macrosomic males. We propose to use our novel model in two strains of mice with different sensitivities to estrogen to examine the interaction between genotype, rate of fetal growth, postnatal nutrition (by using high and low energy feeds), and BPA exposure at human relevant doses during the critical period of adipocyte differentiation in causing different trajectories to adult obesity. We will examine effects of different doses of BPA during development in C57 and CD-1 males and females on growth, fat deposition, insulin and glucose homeostasis, adipocyte number and size, gene expression by qPCR and Next Generation sequencing and DNA methylation in adulthood and on PND 21-28. Our overarching hypothesis is that mouse fetuses with IUGR, macrosomia and normal fetal growth will show differences in the methylation pattern and expression of genes involved in the differentiation, proliferation and regulation of lipogenesis in abdominal adipocytes. In addition, a low maternal oral dose of BPA is predicted to exacerbate obesity in IUGR offspring due to acceleration of postnatal growth. We predict the effects of BPA will be related to differential DNA methylation as well as differential expression of estrogen-responsive genes in adipocytes, and that BPA will lead to a decrease in the number of adipocytes that are functionally altered and prone to hypertrophy. Perinatal exposure to BPA is predicted to interact synergistically with IUGR via additional epigenetic changes in adipocytes that alter the expression of estrogen-responsive genes and further accelerate postnatal growth.

..Jerrold Olefsky. This approach is designed to draw on my strengths as a bench scientist and pediatric endocrinologist, providing an independent focus of research and platform for future R01 funding. ..

..This Program is highly relevant to Superfund by addressing high-priority chemicals and by focusing on mechanisms underlying health effects, exposure assessment, and remediation to mitigate exposure and toxicity. ..